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This new study showing association of SORL1 with late-onset Alzheimer disease (LOAD) provides further support for a role of this gene in AD, confirming earlier studies by Lah, Small, Gandy, Masters, and others implicating SORL1 in AD pathogenesis.

The novelty of this study is the inclusion of genetic association of several SNPs in SORL1 with various samples of different ethnicities. The results for specific SNPs across samples are interesting but inconsistent, with various SNPs showing positive results in some samples and negative data in others. This is often the case for many novel AD candidate genes when tested in multiple samples, either in a single study or across multiple studies.

The Alzgene.org database on Alzforum reveals no less than two dozen genes that exhibit statistically significant association with LOAD after meta-analyses of multiple samples. These can be found in the "Top Alzgene Results" box in the right margin of Alzgene. A full description of Alzgene and its findings can be found in Bertram et al., 2007 in this month's issue.

By statistical analyses on Alzgene prior to this paper, SORL1 would be roughly the twenty-fifth gene to show statistically significant association with LOAD after testing in multiple independent samples. To the authors' credit, a sufficient number of independent samples were tested in this new SORL1 paper to already lend itself to meta-analysis on Alzgene. According to Lars Bertram, these findings are now being added to the site and are summarized here. The bottom line is that several of the meta-analyses for the SORL1 SNPs tested are significant. However, the effect on risk is very modest—the strongest allelic odds ratio for SORL1 is only 1.21. This means that the strongest effect of any SNP in SORL1 in the new study would increase risk for AD by 21 percent. In contrast, one copy of ApoE4 increases risk by about 300 percent.

The top hits on the Alzgene site are ranked by strength of their effect on risk for AD. As expected, ApoE4 is number one. Based on the data in the new study by St George-Hyslop and colleagues, SORL1 would not make the top 10 list, but rank in at number 12 out of 25. So while SORL1 can be added to the list, its small effects on risk based on the multiple case-control samples tested, as well as the less impressive results across the family-based samples tested, would suggest that SORL1 will turn out to be a minor genetic risk factor for AD.

Additional replication testing will be needed to see if the effects on risk hold up over time. As with all AD gene candidates proposed beyond the established four AD genes (APP, PSEN1, PSEN2, ApoE), the true validity of SORL1 as a novel AD gene will need to await the identification of validated pathogenic mutations or variants.

This work is welcome news from an excellent group of investigators. They will surely allow me to play devil’s advocate and caution two things. First, however enticing the cell biology might be, at this point it is a distraction. The question at hand is a genetic question, and to answer the genetics per se, the cell biology data is irrelevant. Unfortunately, journal editors often demand cell biology in genetics papers, even if it’s just an initial set of experiments.

Second, while many sample series were used, there is not an exact replication of the haplotypic association between the sample series, making these "replications," in my view, suspect. In this, the work resembles our own work (Li et al., 2006 and Grupe et al., 2006 on other risk genes). In these cases, too, we obtained multiple, but not entirely convincing replications.

Late-onset Alzheimer genetics is proving to be a very difficult problem. I personally doubt whether this is the new ApoE, but genuine attempts at replication will sort that out reasonably quickly.

Update: With regard to my earlier comment on the SORL1-AD genetic association study by Rogaeva et al, I initially commented that on the Alzgene list of "Top Alzgene Results", SORL1 ranked 12th out of 25 genes. (Ranking is based on effects of SNPs in the gene on risk for AD, with APOE at number 1).

Lars Bertram has now revised that ranking on the most updated "Top Alzgene Results" list:

SORL1 ranks 18th out of 27 genes listed on "Top Alzgene Results" that have statistically significant effects on AD risk following meta-analyses.